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Evidence mounts for alternative origins of Alzheimer’s disease plaques – Neuroscience News

Summary: A new study in mice reveals a breakdown in the process that removes waste from brain cells, before the buildup of amyloid plaques linked to Alzheimer’s disease.

source: New York University Langone Health

A new study in mice shows that the breakdown of how brain cells rid themselves of waste precedes the buildup of debris-laden plaques known to occur in Alzheimer’s disease.

The field has argued for decades that such plaques, which contain the amyloid-beta protein, accumulated outside cells as a critical first step toward the brain damage observed in Alzheimer’s disease. Led by researchers at New York University’s Grossman School of Medicine and the Nathan Klein Institute, the new study challenges this idea, known as the amyloid cascade hypothesis.

The latest study results instead suggest that neuronal damage characteristic of Alzheimer’s disease takes root within cells and before filament-like amyloid plaques form and cluster together in the brain.

Publishing as a magazine cover article natural neuroscience Online on June 2, the study traced the root defect observed in mice bred to develop Alzheimer’s disease to lysosomes in brain cells.

These are tiny sacks inside each cell, filled with acidic enzymes involved in the routine breakdown, removal, and recycling of metabolic waste from everyday cellular interactions, as well as from disease. The researchers note that lysosomes are instrumental in breaking down and getting rid of cell parts when the cell naturally dies.

As part of the study, the researchers tracked the decrease in acidic activity within the lysosomes of healthy mouse cells as the cells became diseased. Imaging tests developed at NYU Langone Health and Nathan Klein (to track the removal of cellular waste) showed that some lysosomes in brain cells became enlarged because they fused with so-called vacuoles filled with undissolved waste. These autophagic vacuoles also contain pre-forms of beta-amyloid.

In neurons that are most damaged and die prematurely as a result, vacuoles cluster together in “flower-like” patterns, bulging out from the cells’ outer membranes and clumping around the center, or nucleus, of each cell. Accumulations of amyloid-beta form filaments within the cell, another hallmark of Alzheimer’s disease. In fact, the researchers observed nearly fully formed plaques inside some of the damaged neurons.

“Our results for the first time trace the damage observed in neurons in Alzheimer’s disease to problems within the corpuscles of brain cells where amyloid-beta first appears,” says study lead author Joo-Hyun Lee, PhD.

says Lee, a research assistant professor in the Department of Psychiatry, Langone Health and New York University, Nathan Klein research scientist.

“This new evidence changes our basic understanding of how Alzheimer’s disease progresses; it also explains why many experimental therapies designed to remove amyloid plaques fail to stop disease progression, because brain cells are already malfunctioning before the plaques can fully form outside the cell,” says the study’s first researcher, Ralph. Nixon, MD, PhD.

“Our research suggests that future treatments should focus on reversing lysosomal dysfunction and rebalancing acid levels within neurons in the brain,” says Nixon, MD, a professor in the Department of Psychiatry and Department of Cell Biology at NYU Langone. Nathan Klein Dementia Research Center.

Three images, as seen by fluorescence microscopy, show flower-like formations (with decreasing resolution) of phagocytic vacuoles in Alzheimer’s mouse neurons. Credit: Springer-Nature Publishing

The researchers say they are already working on experimental therapies to treat the lysosomal problems observed in their studies.

A recent study (published in April in science progress) by the New York University Langone team, the source of one cause of cell waste disposal problems is a gene called PSEN1. The gene has long been known to cause Alzheimer’s disease, but its further role in causing the disease (through lysosomal dysfunction) is only now clear.

Their recent work also demonstrated that neuronal damage in the PSEN1 mouse model of Alzheimer’s disease can be reversed by restoring appropriate acid levels in the lysosomes.

This work covers US Patent No. 9,265,735 which is directed at methods of treating Alzheimer’s disease based on reversal of lysosomal acidification, the primary cause of waste buildup. The terms and conditions of the patent are administered in accordance with health system policies.

According to the National Institute on Aging, more than 6 million Americans, most of them 65 or older, suffer from dementia, the progressive loss of thinking, remembering, and reasoning due to Alzheimer’s disease.

Financing: Funding for these studies was provided by NIH grants P01AG017617, P50AG025688, and R01AG062376.

Besides Lee and Nixon, other researchers at NYU Langone and Nathan Klein who participated in this research are Don Sheng Yang, Chris Goulborn, Ongo M, Philip Stavridis, Ann Pensalvini, Cynthia Bliwas, Martin Berg, Chunfeng Hou, James Bede, Monica Pawlek, Efrat Levi and Mala Rao. Additional co-investigators are Han Chan and Cedric Bouchet-Marquez, at Thermo-Fisher Scientific in Hillsboro, Ore. and Mathias Stauffenbell from the University of Tübingen in Germany.

see also

This indicates a drugged brain

About this research on Alzheimer’s disease news

author: David March
source: New York University Langone Health
Contact: David Marsh – NYU Langone Health
picture: Image credited to Springer-Nature Publishing

original search: open access.
“False autoparticle acidification in mouse models of Alzheimer’s disease induces self-accumulation of Aβ in neurons, resulting in senescent plaques” by Ju-Hyun Lee et al. natural neuroscience


Summary

Faulty autoantibody acidification in mouse models of Alzheimer’s disease leads to autophagic accumulation of Aβ in neurons, which leads to senescent plaques.

Autophagy is significantly impaired in Alzheimer’s disease (AD). Here we reveal a unique defect in intraneuronal autophagy in five AD mouse models in vivo and identify its basis using the mRFP-eGFP-LC3 probe transgenic for autophagy, pH, multifocal imaging and correlative optical electron microscopy.

Acidification of autosomes in neurons decreases well before extracellular amyloid deposition, correlating with markedly reduced vATPase activity and selectively Aβ/APP-βCTF accumulation within amplified deacidified autosomes.

In the most compromised neurons that remain intact, profuse autophagic vacuoles (AVs) assemble into large membranous vesicles forming flower-like rosettes. This unique pattern, called panthos (poisonous anthos (flower)), is also present in AD brains.

Additional anticomplexes combine in perinuclear networks of membranous tubules where fibrillary beta-amyloid protein accumulates within the luminal. It follows permeability of the lysosomal membrane, cathepsin release, and death of lysosomal cells, accompanied by glial invasion.

Quantitative analyzes confirm that individual neurons displaying panthus are the main source of senile plaques in amyloid protein models.

2022-06-02 20:32:37

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